Amyloidosis is the generic term for a number of diseases related by extracellular deposition of insoluble fibrillar proteins (amyloid) in specific organs, which eventually leads to the failure of the involved organs. R. H. Falk et al., The Systemic Amyloidosis, 337 N ENGL J MED 898-909 (1997), P. N. Hawkins, Amyloidosis, 9 BLOOD REV 13542 (1995), J. D. Sipe, Amyloidosis, 31 CR REV CLIN LAB SCI 325-54 (1994); A. S. Cohen, Amyloidosis, 40(2) BULL RHEUM DISEASES 1-12 (1991). Amyloid deposits can remain limited to one organ (localized amyloidosis) or may be more broadly distributed (systemic amyloidosis). Systemic amyloidoses are generally classified into four types based on the nature of the fibrillar deposits: (i.) idiopathic or primary amyloidosis (AL amyloidosis); (ii.) reactive, secondary or amyloid A (AA) amyloidosis; (iii.) familial amyloidotic polyneuropathy; and (iv.) dialysis-associated amyloidosis. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, stain with specific dyes (e.g., Congo red), and have a characteristic birefringent appearance in polarized light after staining. They also share common ultrastructural features and common X-ray diffraction and infrared spectra.
AA amyloidosis is thought to be related to amyloid A (AA) protein formed from the precursor serum amyloid A (SAA), an acute phase protein produced and secreted by hepatocytes in response to inflammation. AA amyloidosis is associated with chronic inflammatory conditions (e.g., rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, etc.), chronic infections (e.g., tuberculosis, osteomyelitis etc.), and hereditary fevers, e.g., Familial Mediterranean Fever (R. H. Falk et al., 337 N ENGL J MED 898-909 (1997), A. S. Cohen, 40(2) BULL RHEUM DISEASES 1-12 (1991), G. Grateau, 12 CURRENT OPINION IN RHEUMATOL 61-64 (2000)). Rheumatoid arthritis is the major cause of AA amyloidosis in Western Europe and North America (M. Skinner Amyloidosis, CURRENT THERAPY IN ALLERGY, IMMUNOLOGY, AND RHEUMATOLOGY 235-40 (Mosby-Year Book Inc., 1996), M. A. Gertz, Secondary amyloidosis, 232 J INT MED 517-18 (1992)).
AA amyloidosis mainly affects parenchymatous organs, such as, kidneys, spleen, liver, and adrenals. The most common clinical feature of AA amyloidosis is renal dysfunction manifested as nephrotic-range proteinuria or renal insufficiency at the time of diagnosis. End-stage renal failure is the cause of death in 40-60% of cases (M. Skinner Amyloidosis, CURRENT THERAPY IN ALLERGY, IMMUNOLOGY, AND RHEUMATOLOGY 235-40 (Mosby-Year Book Inc., 1996), M. A. Gertz, 232 J INT MED 517-18 (1992), M. A. Gertz and R. A. Kyle, 70 MEDICINE 246-256 (1991)). Gastrointestinal involvement is also frequent and is usually manifested as chronic diarrhea, body weight loss and malabsorption. Enlargement of the liver and spleen may also occur in some subjects. Cardiac involvement is rare and occurs late in the disease. The median survival time from diagnosis varies from 2 to 8 years depending on the stage of the disease at time of diagnosis (M. A. Gertz and R. A. Kyle, 70 MEDICINE 246-256 (1991)).
AA amyloidosis is usually seen associated with chronic infection (such as tuberculosis) or chronic inflammation (such as rheumatoid arthritis or hereditary fevers). A familial form of AA amyloidosis is seen Familial Mediterranean Fever (FMF). This familial type of amyloidosis is genetically inherited and is found in specific population groups. In both AL and AA amyloidosis, deposits are found in several organs and are thus considered systemic amyloid diseases.
“Localized amyloidoses” are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob disease, and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disorder, is characterized by neuritic plaques and neurofibrillary tangles. In this case, the amyloid plaques found in the parenchyma and the blood vessel is formed by the deposition of fibrillar Aβ amyloid protein. Other diseases such as adult-onset diabetes (type II diabetes) are characterized by the localized accumulation of amyloid fibrils in the pancreas.
Once these amyloids have formed, there is no known, widely accepted therapy or treatment which significantly dissolves amyloid deposits in situ, prevents further amyloid deposition or prevents the initiation of amyloid deposition.
Each amyloidogenic protein has the ability to undergo a conformational change and to organize into β-sheets and form insoluble fibrils which may be deposited extracellularly or intracellularly. Each amyloidogenic protein, although different in amino acid sequence, has the same property of forming fibrils and binding to other elements such as proteoglycan, amyloid P and complement component. Moreover, each amyloidogenic protein has amino acid sequences which, although different, show similarities such as regions with the ability to bind to the glycosaminoglycan (GAG) portion of proteoglycan (referred to as the GAG binding site) as well as other regions which promote β-sheet formation. Proteoglycans are macromolecules of various sizes and structures that are distributed almost everywhere in the body. They can be found in the intracellular compartment, on the surface of cells, and as part of the extracellular matrix. The basic structure of all proteoglycans is comprised of a core protein and at least one, but frequently more, polysaccharide chains (GAGs) attached to the core protein. Many different GAGs have been discovered including chondroitin sulfate, dermatan sulfate, keratan sulfate, heparin, and hyaluronan.
Some GAG mimetics are known to be useful for inhibiting amyloid deposition and/or treating some forms of amyloidosis. See WO 94/22437, WO 96/28187, and WO 00/64420.